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An Efficacy and Safety Study of Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously Untreated Subjects With Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly Subjects With Acute Myeloid Leukemia (AML)

This study is currently recruiting participants.
See Contacts and Locations
Verified May 2017 by Celgene
Sponsor:
Information provided by (Responsible Party):
Celgene
ClinicalTrials.gov Identifier:
NCT02775903
First received: May 16, 2016
Last updated: May 25, 2017
Last verified: May 2017
  Purpose

This is a Phase 2, multicenter, randomized, parallel-group, open-label study consisting of 3 phases: Screening, Treatment, and Follow-up.

To confirm the safety, ie, the absence of overlapping toxicities of the combination treatment regimen, an early safety monitoring will be performed based on approximately the first 12 subjects randomized.

A total of approximately 72 subjects will be included in the Myelodysplastic syndromes (MDS) cohort and approximately 110 subjects in the Acute Myeloid Leukemia (AML) cohort.


Condition Intervention Phase
Leukemia, Myeloid, Acute Myelodysplastic Syndromes Drug: Azacitidine Drug: Durvalumab Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Randomized, Multicenter, Open-label, Phase 2 Study Evaluating the Efficacy and Safety of Azacitidine Subcutaneous in Combination With Durvalumab (MEDI4736) in Previously Untreated Subjects With Higher-Risk Myelodysplastic Syndromes (MDS) or in Elderly (>= 65 Years) Acute Myeloid Leukemia (AML) Subjects Not Eligible for Hematopoietic Stem Cell Transplantation (HSCT)

Resource links provided by NLM:


Further study details as provided by Celgene:

Primary Outcome Measures:
  • Overall Response Rate (ORR)- MDS(Myelodysplastic syndromes) [ Time Frame: Up to approximately 6 Months ]
    Is defined as percent of subjects with Complete Response (CR), marrow complete remission (mCR), Partial remission (PR), and/or Hematological improvement (HI) as determined using the IWG 2006 response criteria

  • Overall Response Rate (ORR) - AML(Acute myeloid leukemia) [ Time Frame: Up to approximately 6 Months ]
    Is defined as percent of subjects with Complete Response (CR) or Complete remission with incomplete blood recovery (CRi) based on modified IWG 2003 response criteria


Secondary Outcome Measures:
  • Time to response - MDS [ Time Frame: Up to approximately 6 months ]
    Is defined as time from randomization to first documented response according to IWG 2006 response criteria.

  • Relapse-free survival - MDS [ Time Frame: Up to approximately 12 months ]
    Is defined as time from the date CR, PR or mCR is first documented until the date of documented relapse, death from any cause, or lost to follow-up, whichever occurs first according to IWG 2006 response criteria.

  • Cytogenetic response - MDS [ Time Frame: Up to approximately 12 months ]
    Is defined as proportion of subjects achieving complete cytogenetic response or partial cytogenetic response according to IWG 2006 response criteria

  • Progression-free survival (PFS) - MDS [ Time Frame: Up to approximately 12 months ]
    Is defined as time from randomization to the first documented Progressive disease (PD) or death due to any cause, whichever occurs first.

  • Duration of hematologic response- MDS [ Time Frame: Up to approximately 12 months ]
    Is defined as the time from the date response/improvement is first observed until the date the subject has a subsequently documented relapse or disease progression as defined by the IWG 2006 response criteria

  • Time to AML transformation- MDS [ Time Frame: Up to approximately 12 months ]
    Is defined as the time from randomization until the date the subject has transformation to AML

  • Transformation to AML- MDS [ Time Frame: Up to approximately 12 months ]
    Is defined as proportion of subjects having transformation to AML

  • Time to response - AML [ Time Frame: Up to approximately 6 months ]
    Is defined as time from randomization to first documented response based on modified IWG 2003 response criteria

  • Relapse-free survival- AML [ Time Frame: Up to approximately 12 months ]
    Is defined only for subjects who achieve Complete remission (CR) or Complete remission with incomplete blood recovery (CRi) and is measured as the interval from the date of first documented CR or CRi to the date of documented relapse, death from any cause, or lost to follow-up, whichever occurs first

  • Complete cytogenetic response (CyCR)- AML [ Time Frame: Up to approximately 12 months ]
    Is defined as proportion of subjects with complete cytogenetic response (CyCR) based on modified IWG 2003 response criteria

  • Hematologic Improvement Rate - AML [ Time Frame: Up to approximately 12 months ]
    Is defined as rate of Hematological improvement - Neutrophil response (HI-NE) + Hematological improvement - Platelet response (HI-P) + Hematological improvement - Erythroid response (HI-E) according to IWG 2006 response criteria

  • Duration of response - AML [ Time Frame: Up to approximately 12 months ]
    Is defined as the time from the first documented CR/CRi to documented morphologic relapse, PD based on modified IWG 2003 response criteria for AML, or death due to any cause, whichever occurs first.

  • Adverse Events (AEs) - MDS + AML [ Time Frame: Up to approximately 15 months ]
    Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). Adverse event listings will include the verbatim term and the MedDRA preferred term. Adverse events will be graded according to CTCAE Version 4.03 criteria

  • Overall survival - MDS + AML [ Time Frame: Up to approximately 24 months ]
    Is defined as time from randomization to death due to any cause.

  • One-year survival [ Time Frame: Up to approximately 12 months ]
    Is defined as the probability of survival at 1 year from randomization

  • Pharmacokinetics- Cmax [ Time Frame: Up to approximately 231 days ]
    Maximum observed concentration

  • Pharmacokinetics- AUC [ Time Frame: Up to approximately 231 days ]
    Area under the concentration-time curve

  • Pharmacokinetics- Tmax [ Time Frame: Up to approximately 231 days ]
    Time to maximum concentration

  • Pharmacokinetics- t1/2 [ Time Frame: Up to approximately 231 days ]
    Terminal elimination half-life

  • Pharmacokinetics- CL/F [ Time Frame: Up to approximately 231 days ]
    Clearance of distribution

  • Pharmacokinetics- Vz/F [ Time Frame: Up to approximately 231 days ]
    Volume of distribution


Estimated Enrollment: 182
Actual Study Start Date: June 3, 2016
Estimated Study Completion Date: April 16, 2019
Estimated Primary Completion Date: February 11, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Azacitidine in combination with Durvalumab
Subcutaneous azacitidine (75 mg/m2 for 7 days Q4W) in combination with IV durvalumab at a dose of 1500 mg on Day1 Every 4 weeks (Q4W)
Drug: Azacitidine Drug: Durvalumab
Other Name: MEDI4736
Active Comparator: Azacitidine alone
Subcutaneous azacitidine alone at the dose of 75 mg/m2 for 7 days Every 4 weeks (Q4W)
Drug: Azacitidine

Detailed Description:

The enrollment period for this study is expected to last approximately 15 months. The treatment and follow-up periods are expected to conclude approximately 12 months after the last subject is randomized. Therefore, the total duration of the study is expected to be approximately 27 months, from first subject enrolled until the last subject last visit.

Eligible subjects will be randomized to receive subcutaneous azacitidine alone or in combination with durvalumab. The treatment phase will be conducted in 2 stages, with an interim analysis for futility purpose, for each of the 2 study cohorts as outlined in Section 9. The primary analysis will follow completion of Stage 2 with additional analyses conducted approximately 12 months after the last subject is enrolled, as described in Section 9.

Pharmacokinetic (PK) and immunogenicity sampling will be performed in subjects receiving the combination therapy to assess durvalumab PK profile and development of antidrug antibodies.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • For both cohorts:

    1. Subject must understand and voluntarily sign an informed consent form (ICF) prior to any study-related assessments/procedures being conducted.
    2. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
    3. Female subjects of childbearing potential1 may participate, providing they meet the following conditions:

      1. Have 2 negative pregnancy tests as verified by the Investigator prior to starting any IP therapy: serum pregnancy test at screening and negative serum or urine pregnancy test (Investigator's discretion) within 72 hours prior to starting treatment with IP (Cycle 1, Day 1). They must agree to ongoing pregnancy testing during the course of the study (before beginning each subsequent cycle of treatment), and after the last dose of any IP. This applies even if the subject practices complete abstinence[2] from heterosexual contact.
      2. Agree to practice true abstinence2 (which must be reviewed on a monthly basis and source documented) or agree to the use of a highly effective method of contraceptionuse from 28 days prior to starting durvalumab or azacitidine, and must agree to continue using such precautions while taking durvalumab or azacitidine (including dose interruptions) and up to 90 days after the last dose of durvalumab or azacitidine. Cessation of contraception after this point should be discussed with a responsible physician.
      3. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP.

      c. Agree to abstain from breastfeeding during study participation and for at least 90 days after the last dose of IP.

      d. Refrain from egg cell donation while taking durvalumab and for at least 90 days after the last dose of durvalumab.

      A female subject of childbearing potential (FCBP) is a female who:

    1. has achieved menarche at some point
    2. has not undergone a hysterectomy or bilateral oophorectomy or
    3. has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).

      True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.

    4. Male subject must:

    1. Either practice true abstinence3 from heterosexual contact (which must be reviewed on a monthly basis) or agree to avoid fathering a child, to use highly effective methods of contraception, male condom plus spermicide during sexual contact with a pregnant female or a female of childbearing potential (even if he has undergone a successful vasectomy) from starting dose of IP (Cycle 1 Day 1), including dose interruptions through 90 days after receipt of the last dose of durvalumab or azacitidine.
    2. Refrain from semen or sperm donation while taking IP and for at least 90 days after the last dose of IP.

      True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.

      5. Understand and voluntarily sign a biomarker-specific component of the informed consent form prior to any study-related procedures conducted.

      6. Willing and able to adhere to the study visit schedule and other protocol requirements.

      MDS Cohort:

      7. Age ≥ 18 years at the time of signing the informed consent form. 8. Central confirmation of diagnosis of previously untreated primary or secondary Myelodysplastic syndromes (MDS) as per World Health Organization (WHO) classification. Results of central pathology review are required prior to receiving the first dose of IP.

      9. Central confirmation of the categorization of the MDS risk classification, as per the Revised - International prognostic scoring system (IPSS-R) Intermediate risk with >10% blasts or poor or very poor cytogenetics, or IPSS-R High or Very High risk (Results of central pathology review required prior to receiving the first dose of IP).

      Acute myeloid leukemia (AML) Cohort:

      10. Age ≥ 65 years at the time of signing the informed consent form (ICF). 11. Central confirmation of diagnosis of one of the following untreated AML as per WHO classification (Appendix I):

      • Newly diagnosed, histologically confirmed de novo AML (bone marrow blasts ≥ 20%), or
      • AML secondary to prior MDS, or
      • AML secondary to exposure to potentially leukemogenic therapies or agents (eg, radiation therapy, alkylating agents, topoisomerase II inhibitors) with the primary malignancy in remission for at least 2 years.

        12. Central confirmation of intermediate or poor risk status, based on Cytogenetics for Acute Myeloid Leukemia.

      Exclusion Criteria:

  • For both cohorts:

    1. Prior hematopoietic stem cell transplant.
    2. Considered eligible for hematopoietic stem cell transplant (allogeneic or autologous) at the time of signing the ICF.
    3. Prior exposure to azacitidine, decitabine or prior exposure to the investigational oral formulation of decitabine, or other oral azacitidine derivative.
    4. Inaspirable bone marrow.
    5. Use of any of the following within 28 days prior to the first dose of IP:

      • Thrombopoiesis-stimulating agents (eg, romiplostim, eltrombopag, Interleukin-11)
      • Any hematopoietic growth factors (ESAs, Granulocyte colony-stimulating factor (GCSF) and other RBC hematopoietic growth factors (eg, Interleukin-3)
      • Any investigational agents within 28 days or 5 half-lives (whichever is longer) of initiating study treatment
    6. Prior history of malignancies, (except MDS for AML subjects), unless the subject has been free of the disease for ≥ 2 years. However, subjects with the following history/concurrent conditions are allowed:

      • Basal or squamous cell carcinoma of the skin
      • Carcinoma in situ of the cervix
      • Carcinoma in situ of the breast
      • Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [Tumor, node, metastases (TNM)] clinical staging system).
    7. Pregnant or breast-feeding females or females who intend to become pregnant during study participation.
    8. Subject has active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis, Crohn's disease], diverticulitis with the exception of a prior episode that has resolved or diverticulosis, celiac disease, irritable bowel disease [exclude only if active within the last 6 months prior to signing the ICF], or other serious gastrointestinal chronic conditions associated with diarrhea; systemic lupus erythematosus; Wegener's syndrome [granulomatosis with polyangiitis]; myasthenia gravis; Graves' disease; rheumatoid arthritis; hypophysitis, uveitis; etc) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion:

      • Subjects with vitiligo or alopecia;
      • Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement for ≥ 3 months prior to signing the ICF; or
      • Subjects with psoriasis not requiring systemic treatment
    9. Significant active cardiac disease within the previous 6 months prior to signing the ICF, including:

      • New York Heart Association (NYHA) Class III or IV congestive heart failure;
      • Unstable angina or angina requiring surgical or medical intervention; and/or
      • Significant cardiac arrhythmia
      • Myocardial infarction
    10. Uncontrolled intercurrent illness including, but not limited to, ongoing or active systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment), uncontrolled hypertension, cardiac arrhythmia, pneumonitis, interstitial lung disease, active peptic ulcer disease or gastritis that would limit compliance with study requirement.
    11. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection.
    12. Known or suspected hypersensitivity to azacitidine, mannitol, or durvalumab, its constituents, or to any other humanized monoclonal antibody.
    13. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
    14. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
    15. Prior anti- Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), Programmed death-1 (PD-1), or Programmed death ligand-1 (PD-L1) or other immune checkpoint mAb exposure.
    16. Other investigational mAbs within 6 months prior to first dose of IP.
    17. Current or prior use of immunosuppressive medication within 14 days prior to the first dose of IP. The following are exceptions to this criterion:

      • Intranasal, inhaled, topical, or local steroid injections (eg, intra-articular injection)
      • Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
      • Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication)
    18. History of primary immunodeficiency.
    19. Receipt of live, attenuated vaccine within 30 days prior to the first dose of IP (NOTE: Subjects, if enrolled, should not receive live vaccine during the study and for 30 days after the last dose of durvalumab).
    20. Unwilling or unable to complete subject reported outcome assessments without assistance or with minimal assistance from trained site personnel and/or caregiver.
    21. Subjects who have had clinical evidence of central nervous system (CNS) or pulmonary leukostasis, disseminated intravascular coagulation, or CNS leukemia.
    22. Presence of advanced malignant hepatic tumors.
    23. Any of the following laboratory abnormalities:

      • Serum aspartate aminotransferase (AST/SGOT) or alanine aminotransferase (ALT/SGPT) > 2.5 × upper limit of normal (ULN)
      • Serum total bilirubin > 1.5 × ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs' test or over 50% of indirect bilirubin
      • Serum creatinine > 2.5 × ULN.

      MDS Cohort:

    24. Any previous cytotoxic, cytostatic, hormonal, biological or immunological treatment for MDS (Erythropoietin-stimulating agent (ESA) with or without granulocyte colony stimulating factor (G-CSF) are allowed under certain conditions, see exclusion criterion # 5).
    25. Any investigational therapy within 28 days prior to the first dose of IP.
    26. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample and prior to first dose of IP.
    27. Absolute WBC count ≥ 15 × 109/L.

      AML Cohort:

    28. Previous cytotoxic, cytostatic, hormonal, biological or immunological treatment (ESA with or without G-CSF and iron chelating therapy and hydroxyurea are allowed under certain conditions, see exclusion criterion #5) or biologic treatment for AML.
    29. Any investigational therapy within 28 days prior to the first dose of IP.
    30. Use of hydroxyurea within 2 weeks prior to obtaining the screening hematology sample and prior to first dose of IP.
    31. Prior use of targeted therapy agents (eg, FLT3 inhibitors, other kinase inhibitors).
    32. Suspected or proven acute promyelocytic leukemia (French-American-British (FAB) M3) based on morphology, immunophenotype, molecular assay, or karyotype; AML associated with t(9;22) karyotype, biphenotypic acute leukemia or AML with previous hematologic disorder such as chronic myelogenous leukemia or myeloproliferative neoplasms.
    33. Acute myeloid leukemia associated with inv(16), t(8;21), t(16;16), t(15;17) karyotypes or molecular evidence of such translocations if not associated with a c-Kit mutation.
    34. Absolute White blood cell (WBC) count ≥ 15 × 109/L (NOTE: Hydroxyurea is not allowed to attain a WBC count ≤ 15 x 109/L).
    35. Known history or presence of Sweet Syndrome at screening
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02775903

Contacts
Contact: Associate Director Clinical Trial Disclosure 1-888-260-1599 clinicaltrialdisclosure@celgene.com

  Show 92 Study Locations
Sponsors and Collaborators
Celgene
Investigators
Study Director: CL Beach, Pharm D Celgene Corporation
  More Information

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT02775903     History of Changes
Other Study ID Numbers: MEDI4736-MDS-001
Study First Received: May 16, 2016
Last Updated: May 25, 2017

Keywords provided by Celgene:
MEDI4736
Durvalumab
Myelodysplastic Syndromes
Acute Myeloid Leukemia
Hematopoietic Stem Cell Transplantation
Azacitidine
Safety
Efficacy
PD-L1

Additional relevant MeSH terms:
Syndrome
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Disease
Pathologic Processes
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Azacitidine
Antibodies, Monoclonal
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on June 22, 2017